Abstract 6555: Integrated bioinformatics analysis identified ASNS and DDIT3 as the therapeutic target in castration resistance prostate cancer
Authors: Ae Ryang Jung, Sun Shin, U-Syn Ha, Mee Young Kim, Sung-Hoo Hong, Ji Youl Lee, Sae Woong Kim, Yeun-Jun Chung, Yong Hyun Park
Journal: Cancer Research (2023)

Abstract Background: Many studies have demonstrated the mechanisms of progression to castration-resistant prostate cancer (CRPC) and novel strategies for the treatment of CRPC. Despite these advances, the molecular mechanism underlying the progression to CRPC remain unclear, and no effective treatments for CRPC are currently available. Here, we characterized the pathways and key genes involved in the progression to CRPC to gain insight into the mechanisms and potential therapeutic targets of CRPC. Methods: Bicalutamide-resistant prostate cancer cells derived from LNCaP was generated and named Bical R. RNA sequencing was used to identify differentially expressed genes (DEGs) between LNCaP and Bical R. DAVID and Clue GO were used to perform functional enrichment analysis, and the Cytohubba plug-in Cytoscape was used to identify hub genes associated with progression to CRPC. To validate the expression of hub genes, we performed qRT-PCR and western blot analyses. Further validation was performed using GEO microarray (GSE 32269 and GSE28403). To elucidate the clinical usefulness of these genes, we assessed the disease-free survival of patients with prostate cancer from The Cancer Genome Atlas (TCGA) database. Results: In total, 631 DEGs (302 upregulated genes and 329 downregulated genes) were identified, and Kyoto Encyclopedia of Genes and Genomes pathways were analyzed based on DAVID and Clue GO. We found that the PI3K-Akt and MAPK signaling pathways are of great significance for investigating the mechanism of CRPC progression. Hub genes from protein-protein interaction network of upregulated DEGs (AGT, ASNS, ATF3, ATF4, DDIT3, EFNA5, and VEGFA) were identified. Among the hub genes, ASNS and DDIT3 were markedly up-regulated in CRPC cell lines and CRPC tissues, respectively. Additionally, patients with high expression of ASNS and DDIT3 showed worse disease-free survival in TCGA database. Conclusion: Our study revealed that the PI3K-Akt and MAPK signaling pathways may be important in the mechanism of CRPC progression, and ASNS and DDIT3 may be associated with progression to CRPC. These results may contribute to the development of potential therapeutic targets and mechanisms underlying the progression to CRPC to improve clinical efficacy for CRPC treatment. Acknowledgements: This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (No. 2022R1A2C2003513). Citation Format: Ae Ryang Jung, Sun Shin, U-Syn Ha, Mee Young Kim, Sung-Hoo Hong, Ji Youl Lee, Sae Woong Kim, Yeun-Jun Chung, Yong Hyun Park. Integrated bioinformatics analysis identified ASNS and DDIT3 as the therapeutic target in castration resistance prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6555.